JAMM Deubiquitinating Enzymes in Disease: Comparison
Please note this is a comparison between Version 3 by Vivi Li and Version 2 by Vivi Li.

Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory diseases at multiple levels. The far smaller numbers and distinct catalytic mechanism of JAMMs render them attractive drug targets. Several JAMM inhibitors have been successfully developed and have shown promising therapeutic efficacy. 

  • deubiquitinating enzymes
  • JAMMs
  • structural basis
  • catalytic mechanism
  • functions
  • inhibitors

1. Introduction

Protein ubiquitination, defined as a process that covalently conjugates ubiquitin to the target protein, is one of the most powerful post-translational modifications regulating virtually all cellular processes, such as cell death, cell cycle, and DNA repair [1][2][3][4]. Ubiquitin is a 76-amino-acid, 8-kDa polypeptide with a conserved sequence that is present universally and ubiquitously in eukaryotes [5][6]. Full-length ubiquitin contains eight ubiquitination sites, including seven lysine residues (K6, K11, K27, K29, K33, K48, K63) and an N-terminal methionine residue (M1) (Figure 1A) [7][8]. Under the sequential action of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3), an isopeptide linkage is formed between the carboxyl group of the ubiquitin C-terminal glycine and the ε-amino group of the target protein lysine (Figure 1B) [9][10]. Then, the Gly 76 of additional ubiquitin molecules (called distal ubiquitin) can be covalently attached to the ubiquitination sites in ubiquitin itself (called proximal ubiquitin), to produce polyubiquitin chains [11]. As a result, various types of protein ubiquitination are formed, which determine the fate of ubiquitinated substrates [6][12]. For example, polyubiquitin chains linked via the K48 of internal ubiquitin groups are used for protein degradation signaling by the ubiquitin-proteasome system (Figure 1C1,C2), whereas K63-linked polyubiquitin chains, presenting different architecture, play proteasome-independent roles in various intracellular events, such as inflammatory signaling, DNA repair, ribosomal protein synthesis, endocytosis, and vesicular trafficking (Figure 1D1,D2) [13][14][15]. Additionally, some other ubiquitin-like modifications, such as small ubiquitin-like modifier (SUMO), neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8), and interferon stimulated gene 15 (ISG15), can also be ligated to target proteins in a process similar to ubiquitylation, mostly to provide nondegradative signals [16].
Figure 1. (A) Crystal structure of human ubiquitin (PDB ID: 1UBQ). Seven lysine residues and an N-terminal methionine residue are colored green and yellow, respectively. (B) The isopeptide bond between the ubiquitin glycine residue (orange) and the target protein lysine residue (blue). (C1,C2) The overall structure and local conformation of K48-linked polyubiquitin chains (PDB ID: 1TBE). (D1,D2) The overall structure and local conformation of K63-linked polyubiquitin chains (PDB ID: 3HM3). The distal and proximal ubiquitin are colored gray and cyan, respectively.
To date, the human genome encodes nearly 600 E3 ligases while only approximately 100 deubiquitinating enzymes (DUBs) have been identified, clustered in the following 7 families: 56 ubiquitin-specific peptidases (USPs), 17 ovarian tumor proteases (OTUs), 12 JAB1/MPN/Mov34 metalloenzymes (JAMMs), 5 motif interacting with ubiquitin-containing novel DUB family proteases (MINDYs), 4 ubiquitin C-terminal hydroxylases (UCHs), 4 Machado-Josephin domain proteases (MJDs), and 1 zinc finger-containing ubiquitin peptidase 1 (ZUP1) [17][18][19]. Six of these seven families are cysteine proteases, whereas only the JAMM family are zinc-dependent metalloproteinases. In the case of cysteine protease DUBs, the catalytic domains contain a highly conserved catalytic triad comprising cysteine and nearby histidine and aspartate residues [8][20]. In contrast, metalloprotease DUBs coordinate Zn2+ ion with histidine, aspartate, and serine residues to attack the isopeptide bond by activating a water molecule [21].
Dysfunction of the ubiquitin system, especially DUBs, has been recognized as a contributing factor in the origin of many human diseases, such as cancer, inflammatory diseases, and neurological diseases [22][23]. Notably, there has been a recent expansion of drug discovery programs targeting JAMMs. Unlike the large number of cysteine protease DUBs (~90), as few as 12 JAMMs have been identified in the human genome, among which only 7 (AMSH, AMSH-LP, BRCC36, eIF3h, Rpn11, MYSM1, and CSN5) exhibit isopeptidase activity toward ubiquitin chains [17][24]. Furthermore, multiple JAMM-related signaling pathways, such as DNA damage control (BRCC36) [25], endocytosis (AMSH, AMSH-LP) [26][27], protein biosynthesis (eIF3h) [28], and protein degradation (Rpn11, CSN5) [29], have been confirmed to be associated with numerous diseases, including tumorigenesis and immunological and inflammatory disorders. The much fewer numbers, distinct catalytic mechanism, and, specifically, association with diseases render JAMMs a new class of potential drug targets [30]. To gain an in-depth understanding of JAMMs, this entry emphatically discusses the structural basis, catalytic mechanism, and diverse functions with a focus on JAMM family proteins, including AMSH, AMSH-LP, BRCC36, Rpn11, and CSN5. Researchers also summarize the current reported inhibitors targeting JAMM family members.

2. Structural Characteristic of JAMMs

The MPN (Mpr1/Pad1 N-terminal) domain is a striking characteristic of the JAMM family. In 2004, Ambroggio et al. first reported the crystal structure of the MPN domain protein (PDB ID: 1R5X) from a prokaryotic organism Archaeoglobus fulgidus AF2198 (AfJAMM) [31]. They revealed that the MPN domain of AfJAMM consisted of an eight-stranded β sheet (β1–β8), flanked by a long α helix (α1) between the first and second strand, and a short α helix (α2) between the fourth and fifth strand (Figure 2A). Subsequently, an increasing number of crystal structures were resolved and the MPN domain proteins could then be further divided into two subfamilies: (1) the MPN+ family, with isopeptidase activity, characterized by a zinc-coordinating JAMM motif (ExnHxHx7Sx2D) (where x represents any amino acid residue) (Figure 2K); and (2) the MPN– family, without catalytic activity, serving as scaffolds in some JAMM multi-subunit complexes [32][33][34].
Figure 2. Structural characteristics of JAMM MPN domain mentioned in this entry. (A) Crystal structure of AfJAMM (PDB ID: 1R5X). AfJAMM has a typical MPN domain containing an eight-stranded β sheet (β1–β8) (fuchsia), a long α helix (α1), and a short α helix (α2) (cyan). (BJ) Crystal structure of AMSH (PDB ID: 3RZU) (light blue), AMSH-LP (PDB ID: 2ZNV) (wheat), BRCC36 (PDB ID: 6H3C) (light pink), CSN5 (PDB ID: 4F7O) (pale cyan), Rpn11 (PDB ID: 4O8X) (gray), Abro1 (PDB ID: 6H3C) (sand), CSN6 (PDB ID: 4D10) (salmon), Rpn8 (PDB ID: 4O8X) (light black), and Abraxas (PDB ID: 6GVW) (slate) MPN domain. All the Ins-1 and Ins-2 loop are colored deep green and blue, respectively. The yellow and green asterisks represent active sites of MPN+ and MPN–, respectively. The black round represents Zn2+ ion. (K) The zinc-coordinating JAMM motif of MPN+ (ExnHxHx7Sx2D) (where x is any amino acid residue).
Most JAMMs possess two unique insertions, referred to as Ins-1 and Ins-2, which are considered to play important roles in the recognition and binding of ubiquitinated protein substrates [24]. The Ins-1 segment forms one ridge of the substrate-binding groove to assist in the proper positioning of the C-terminal ubiquitin tail for catalysis while the Ins-2 region contributes to the productive substrate positioning [35].

3. Catalytic Mechanism of JAMMs

So far, 7 of the 12 JAMMs (AMSH, AMSH-LP, BRCC36, eIF3h, Rpn11, CSN5, and MYSM1) in the human genome belong to the MPN+ subfamily and have DUB activity toward proteins while the remaining 5 JAMMs (Abraxas, Abro1, CSN6, eIF3f, and Rpn8) belong to the MPN− subfamily [36][37]. Interestingly, most of these JAMMs require the formation of multi-subunit complexes to exert their isopeptidase activities, including Rpn11 and Rpn8 of the 26S proteasome [29], CSN5 and CSN6 of the COP9 signalosome [38], eIF3f and eIF3h of the human translation initiation factor 3 (eIF3) [39], BRCC36 and Abraxas of the BRCA1-A complex [40], and BRCC36 and Abro1 of the BRISC complex [41]. There are, of course, exceptions, such as AMSH and AMSH-LP, which can cleave K63-linked ubiquitin chains independent of protein partners [42]. Sato et al. resolved the crystal structure of AMSH-LPE292A-ubiquitin complex (PDB ID: 2ZNV) from H. sapiens and proposed the catalytic mechanism of JAMMs, which was probably similar to that of thermolysin [26][43]. First, the zinc-bound catalytic water is deprotonated by an active site Glu 292 and subsequently performs a nucleophilic attack on the substrate peptide carbonyl. Then, the negative charge on the peptide carbonyl oxygen is stabilized by the Zn2+ ion and His 347, His 349, Ser 357, and Asp 360 while the positive charge on the amide nitrogen is stabilized by Glu 292. The reaction then proceeds through an oxyanion tetrahedral intermediate and a second transition state, which results in the cleavage of the peptide N-C bond. With the proton transferring from the amide nitrogen to water, the cleavage of the peptide bond is ultimately completed [26]. Although the whole amino acid sequences of these seven MPN+ members are highly divergent, the catalytic core region is completely conserved, suggesting that they might employ identical catalytic mechanisms [30].

4. Structural and Functional Basis of JAMMs

4.1. Functional Basis of AMSH in Receptor Endocytosis

It has recently been shown that AMSH plays a significant role in regulating the endosomal sorting of many cell-surface receptors, which is a highly regulated process for maintaining cellular homeostasis and generating adaptive responses to external stimuli [44][45]. Typically, the endocytic trafficking process involves the internalization, endosomal sorting, and lysosomal degradation of cell-surface receptors and is strictly executed by the endosomal sorting complexes required for transport (ESCRT), consisting of at least five macromolecular assemblies termed ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III and vacuolar sorting protein 4 (Vps4) [46][47][48]. It is during this process that AMSH can interact with the components ESCRT-0 and ESCRT-III and so affect the fate of receptors [16]. Several studies have documented the crucial role of AMSH-mediated deubiquitination in the trafficking of endocytosed receptors, such as receptor-tyrosine kinase epidermal growth factor receptor (EGFR), G protein-coupled receptors (GPCRs), connexins 43 (connexin Cx43), and the inflammasome component NACHT, LRR, and PYD domain-containing protein (NALP7) (Table 1) [49][50][51][52][53][54]. For example, the E3-ligase c-Cbl has been shown to promote lysosomal degradation of the K63 ubiquitylated EGFR [55] while AMSH opposes this action and promotes EGFR recycling, thus regulating the balance of the intracellular EGFR content [51]. In another study, Ribeiro-Rodrigues et al. demonstrated that AMSH could protect gap junctions from degradation by mediating the deubiquitination of Cx43 to regulate intercellular communication [52]. By linking the DUBs to immune regulation, Mallampalli et al. found that AMSH cleaved K63-linked ubiquitin from NALP7 to increase its intracellular content, leading to inflammasome-dependent IL-1β cleavage and release [54]. For some important GPCRs, including chemokine receptor CXCR4, protease-activated receptor 2 (PAR2), and δ-opioid receptor (DOR), AMSH has been reported to regulate their stability and trafficking, as the loss of AMSH catalytic activity can significantly alter the steady-state level of GPCRs [49][50][53]. Overall, AMSH-mediated receptor endocytosis is accomplished through the recognition of specific ubiquitination patterns, specifically multi-monoubiquitination and K63-linked polyubiquitination.

References

  1. Imai, Y.; Soda, M.; Takahashi, R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J. Biol. Chem. 2000, 275, 35661–35664.
  2. Karin, M.; Ben-Neriah, Y. Phosphorylation meets ubiquitination: The control of NF-B activity. Annu. Rev. Immunol. 2000, 18, 621–663.
  3. Pagano, M.; Tam, S.W.; Theodoras, A.M.; Beer-Romero, P.; Del Sal, G.; Chau, V.; Yew, P.R.; Draetta, G.F.; Rolfe, M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995, 269, 682–685.
  4. Glickman, M.H.; Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiol. Rev. 2002, 82, 373–428.
  5. Akutsu, M.; Dikic, I.; Bremm, A. Ubiquitin chain diversity at a glance. J. Cell Sci. 2016, 129, 875–880.
  6. Komander, D.; Rape, M. The ubiquitin code. Annu. Rev. Biochem. 2012, 81, 203–229.
  7. Yau, R.; Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 2016, 18, 579–586.
  8. Komander, D.; Clague, M.J.; Urbé, S. Breaking the chains: Structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 2009, 10, 550–563.
  9. Swatek, K.N.; Komander, D. Ubiquitin modifications. Cell Res. 2016, 26, 399–422.
  10. Hershko, A.; Ciechanover, A.; Varshavsky, A. Basic medical research award. The ubiquitin system. Nat. Med. 2000, 6, 1073–1081.
  11. Pickart, C.M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 2001, 70, 503–533.
  12. Kwon, Y.T.; Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 2017, 42, 873–886.
  13. Hospenthal, M.K.; Freund, S.M.; Komander, D. Assembly, analysis and architecture of atypical ubiquitin chains. Nat. Struct. Mol. Biol. 2013, 20, 555–565.
  14. Ye, Y.; Blaser, G.; Horrocks, M.H.; Ruedas-Rama, M.J.; Ibrahim, S.; Zhukov, A.A.; Orte, A.; Klenerman, D.; Jackson, S.E.; Komander, D. Ubiquitin chain conformation regulates recognition and activity of interacting proteins. Nature 2012, 492, 266–270.
  15. Erpapazoglou, Z.; Walker, O.; Haguenauer-Tsapis, R. Versatile roles of k63-linked ubiquitin chains in trafficking. Cells 2014, 3, 1027–1088.
  16. Clague, M.J.; Urbé, S. Endocytosis: The DUB version. Trends Cell Biol. 2006, 16, 551–559.
  17. Schauer, N.J.; Magin, R.S.; Liu, X.; Doherty, L.M.; Buhrlage, S.J. Advances in discovering deubiquitinating enzyme (DUB) inhibitors. J. Med. Chem. 2020, 63, 2731–2750.
  18. Kwasna, D.; Abdul Rehman, S.A.; Natarajan, J.; Matthews, S.; Madden, R.; De Cesare, V.; Weidlich, S.; Virdee, S.; Ahel, I.; Gibbs-Seymour, I.; et al. Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Mol. Cell 2018, 70, 150–164.e156.
  19. Mevissen, T.E.T.; Komander, D. Mechanisms of deubiquitinase specificity and regulation. Annu. Rev. Biochem. 2017, 86, 159–192.
  20. Hanpude, P.; Bhattacharya, S.; Dey, A.K.; Maiti, T.K. Deubiquitinating enzymes in cellular signaling and disease regulation. IUBMB Life 2015, 67, 544–555.
  21. Sowa, M.E.; Bennett, E.J.; Gygi, S.P.; Harper, J.W. Defining the human deubiquitinating enzyme interaction landscape. Cell 2009, 138, 389–403.
  22. Gadhave, K.; Kumar, P.; Kapuganti, S.K.; Uversky, V.N.; Giri, R. Unstructured biology of proteins from ubiquitin-proteasome system: Roles in cancer and neurodegenerative diseases. Biomolecules 2020, 10, 796.
  23. Cockram, P.E.; Kist, M.; Prakash, S.; Chen, S.H.; Wertz, I.E.; Vucic, D. Ubiquitination in the regulation of inflammatory cell death and cancer. Cell Death Differ. 2021, 28, 591–605.
  24. Ronau, J.A.; Beckmann, J.F.; Hochstrasser, M. Substrate specificity of the ubiquitin and Ubl proteases. Cell Res. 2016, 26, 441–456.
  25. Patterson-Fortin, J.; Shao, G.; Bretscher, H.; Messick, T.E.; Greenberg, R.A. Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. J. Biol. Chem. 2010, 285, 30971–30981.
  26. Sato, Y.; Yoshikawa, A.; Yamagata, A.; Mimura, H.; Yamashita, M.; Ookata, K.; Nureki, O.; Iwai, K.; Komada, M.; Fukai, S. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 2008, 455, 358–362.
  27. McCullough, J.; Clague, M.J.; Urbé, S. AMSH is an endosome-associated ubiquitin isopeptidase. J. Cel. Biol. 2004, 166, 487–492.
  28. Marchione, R.; Leibovitch, S.A.; Lenormand, J.L. The translational factor eIF3f: The ambivalent eIF3 subunit. Cell Mol. Life Sci. 2013, 70, 3603–3616.
  29. Verma, R.; Aravind, L.; Oania, R.; McDonald, W.H.; Yates, J.R.; Koonin, E.V.; Deshaies, R.J. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 2002, 298, 611–615.
  30. Birol, M.; Echalier, A. Structure and function of MPN (Mpr1/PadN-terminal) domain-containing proteins. Curr. Protein Pept. Sci. 2014, 15, 504–517.
  31. Ambroggio, X.I.; Rees, D.C.; Deshaies, R.J. JAMM: A metalloprotease-like zinc site in the proteasome and signalosome. PLoS Biol. 2004, 2, 0113–0119.
  32. Dambacher, C.M.; Worden, E.J.; Herzik, M.A.; Martin, A.; Lander, G.C. Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. eLife 2016, 5, e13027.
  33. Galej, W.P.; Nguyen, T.H.D.; Newman, A.J.; Nagai, K. Structural studies of the spliceosome: Zooming into the heart of the machine. Curr. Opin. Struct. Biol. 2014, 25, 57–66.
  34. Lingaraju, G.M.; Bunker, R.D.; Cavadini, S.; Hess, D.; Hassiepen, U.; Renatus, M.; Fischer, E.S.; Thomä, N.H. Crystal structure of the human COP9 signalosome. Nature 2014, 512, 161–165.
  35. Shrestha, R.K.; Ronau, J.A.; Davies, C.W.; Guenette, R.G.; Strieter, E.R.; Paul, L.N.; Das, C. Insights into the mechanism of deubiquitination by JAMM deubiquitinases from cocrystal structures of the enzyme with the substrate and product. Biochemistry 2014, 53, 3199–3217.
  36. Fraile, J.M.; Quesada, V.; Rodríguez, D.; Freije, J.M.P.; López-Otín, C. Deubiquitinases in cancer: New functions and therapeutic options. Oncogene 2012, 31, 2373–2388.
  37. Maytal-Kivity, V.; Reis, N.; Hofmann, K.; Glickman, M.H. MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function. BMC Biochem. 2002, 3, 28.
  38. Liu, Y.; Shah, S.V.; Xiang, X.; Wang, J.; Deng, Z.-B.; Liu, C.; Zhang, L.; Wu, J.; Edmonds, T.; Jambor, C.; et al. COP9-associated CSN5 regulates exosomal protein deubiquitination and sorting. Am. J. Pathol. 2009, 174, 1415–1425.
  39. Iadevaia, V.; Caldarola, S.; Tino, E.; Amaldi, F.; Loreni, F. All translation elongation factors and the e, f, and h subunits of translation initiation factor 3 are encoded by 5′-terminal oligopyrimidine (TOP) mRNAs. RNA 2008, 14, 1730–1736.
  40. Dong, Y.; Hakimi, M.-A.; Chen, X.; Kumaraswamy, E.; Cooch, N.S.; Godwin, A.K.; Shiekhattar, R. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol. Cell 2003, 12, 1087–1099.
  41. Zeqiraj, E.; Tian, L.; Piggott, C.A.; Pillon, M.C.; Duffy, N.M.; Ceccarelli, D.F.; Keszei, A.F.A.; Lorenzen, K.; Kurinov, I.; Orlicky, S.; et al. Higher-order assembly of BRCC36-KIAA0157 is required for DUB activity and biological function. Mol. Cell 2015, 59, 970–983.
  42. Nakamura, M.; Tanaka, N.; Kitamura, N.; Komada, M. Clathrin anchors deubiquitinating enzymes, AMSH and AMSH-like protein, on early endosomes. Genes Cells 2006, 11, 593–606.
  43. Holden, H.M.; Tronrud, D.E.; Monzingo, A.F.; Weaver, L.H.; Matthews, B.W. Slow- and fast-binding inhibitors of thermolysin display different modes of binding: Crystallographic analysis of extended phosphonamidate transition-state analogues. Biochemistry 1987, 26, 8542–8553.
  44. Wright, M.H.; Berlin, I.; Nash, P.D. Regulation of endocytic sorting by ESCRT-DUB-mediated deubiquitination. Cell Biochem. Biophys. 2011, 60, 39–46.
  45. Kyuuma, M.; Kikuchi, K.; Kojima, K.; Sugawara, Y.; Sato, M.; Mano, N.; Goto, J.; Takeshita, T.; Yamamoto, A.; Sugamura, K.; et al. AMSH, an ESCRT-III associated enzyme, deubiquitinates cargo on MVB/late endosomes. Cell Struct. Funct. 2007, 31, 159–172.
  46. Agromayor, M.; Martin-Serrano, J. Interaction of AMSH with ESCRT-III and deubiquitination of endosomal cargo. J. Biol. Chem. 2006, 281, 23083–23091.
  47. Shields, S.B.; Piper, R.C. How ubiquitin functions with ESCRTs. Traffic 2011, 12, 1306–1317.
  48. Henne, W.M.; Stenmark, H.; Emr, S.D. Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb. Perspect. Biol. 2013, 5, 1288–1302.
  49. Hasdemir, B.; Murphy, J.E.; Cottrell, G.S.; Bunnett, N.W. Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor. J. Biol. Chem. 2009, 284, 28453–28466.
  50. Hislop, J.N.; Henry, A.G.; Marchese, A.; von Zastrow, M. Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomes. J. Biol. Chem. 2009, 284, 19361–19370.
  51. Meijer, I.M.J.; van Rotterdam, W.; van Zoelen, E.J.J.; van Leeuwen, J.E.M. Recycling of EGFR and ErbB2 is associated with impaired Hrs tyrosine phosphorylation and decreased deubiquitination by AMSH. Cell. Signal. 2012, 24, 1981–1988.
  52. Ribeiro-Rodrigues, T.M.; Catarino, S.; Marques, C.; Ferreira, J.V.; Martins-Marques, T.; Pereira, P.; Girão, H. AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions. FASEB J. 2014, 28, 4629–4641.
  53. Sierra, M.I.; Wright, M.H.; Nash, P.D. AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR. J. Biol. Chem. 2010, 285, 13990–14004.
  54. Bednash, J.S.; Weathington, N.; Londino, J.; Rojas, M.; Gulick, D.L.; Fort, R.; Han, S.; McKelvey, A.C.; Chen, B.B.; Mallampalli, R.K. Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity. Nat. Commun. 2017, 8, 15203.
  55. Levkowitz, G.; Waterman, H.; Zamir, E.; Kam, Z.; Oved, S.; Langdon, W.Y.; Beguinot, L.; Geiger, B.; Yarden, Y. c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev. 1998, 12, 3663–3674.
  56. Py, B.F.; Kim, M.-S.; Vakifahmetoglu-Norberg, H.; Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 2013, 49, 331–338.
  57. Zheng, H.; Gupta, V.; Patterson-Fortin, J.; Bhattacharya, S.; Katlinski, K.; Wu, J.; Varghese, B.; Carbone, C.J.; Aressy, B.; Fuchs, S.Y.; et al. A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep. 2013, 5, 180–193.
  58. Xu, M.; Moresco, J.J.; Chang, M.; Mukim, A.; Smith, D.; Diedrich, J.K.; Yates, J.R.; Jones, K.A. SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1Tat K63-ubiquitylation and destruction by autophagy. PLoS Pathog. 2018, 14, e1007071.
  59. Yan, K.; Li, L.; Wang, X.; Hong, R.; Zhang, Y.; Yang, H.; Lin, M.; Zhang, S.; He, Q.; Zheng, D.; et al. The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J. Cell Biol. 2015, 210, 209–224.
  60. Donaghy, R.; Han, X.; Rozenova, K.; Lv, K.; Jiang, Q.; Doepner, M.; Greenberg, R.A.; Tong, W. The BRISC deubiquitinating enzyme complex limits hematopoietic stem cell expansion by regulating JAKK63-ubiquitination. Blood 2019, 133, 1560–1571.
  61. Shao, G.; Lilli, D.R.; Patterson-Fortin, J.; Coleman, K.A.; Morrissey, D.E.; Greenberg, R.A. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc. Natl. Acad. Sci. USA 2009, 106, 3166–3171.
  62. Nabhan, J.F.; Ribeiro, P. The 19S proteasomal subunit POH1 contributes to the regulation of c-Jun ubiquitination, stability, and subcellular localization. J. Biol. Chem. 2006, 281, 16099–16107.
  63. Wang, B.; Ma, A.; Zhang, L.; Jin, W.-L.; Qian, Y.; Xu, G.; Qiu, B.; Yang, Z.; Liu, Y.; Xia, Q.; et al. POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation. Nat. Commun. 2015, 6, 8704.
  64. Liu, H.; Buus, R.; Clague, M.J.; Urbé, S. Regulation of ErbB2 receptor status by the proteasomal DUB POH1. PLoS ONE 2009, 4, e5544.
  65. Butler, L.R.; Densham, R.M.; Jia, J.; Garvin, A.J.; Stone, H.R.; Shah, V.; Weekes, D.; Festy, F.; Beesley, J.; Morris, J.R. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO J. 2012, 31, 3918–3934.
  66. Schwarz, T.; Sohn, C.; Kaiser, B.; Jensen, E.D.; Mansky, K.C. The 19S proteasomal lid subunit POH1 enhances the transcriptional activation by Mitf in osteoclasts. J. Cell. Biochem. 2010, 109, 967–974.
  67. Cope, G.A.; Deshaies, R.J. COP9 signalosome: A multifunctional regulator of SCF and other cullin-based ubiquitin ligases. Cell 2003, 114, 663–671.
  68. Polo, S. Signaling-mediated control of ubiquitin ligases in endocytosis. BMC. Biol. 2012, 10, 25.
  69. McCullough, J.; Row, P.E.; Lorenzo, O.; Doherty, M.; Beynon, R.; Clague, M.J.; Urbé, S. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr. Biol. 2006, 16, 160–165.
  70. Davies, C.W.; Paul, L.N.; Das, C. Mechanism of recruitment and activation of the endosome-associated deubiquitinase AMSH. Biochemistry 2013, 52, 7818–7829.
  71. Hologne, M.; Cantrelle, F.-X.; Riviere, G.; Guillière, F.; Trivelli, X.; Walker, O. NMR reveals the interplay among the AMSH SH3 binding motif, STAM2, and Lys63-linked diubiquitin. J. Mol. Biol. 2016, 428, 4544–4558.
  72. Azmi, I.F.; Davies, B.A.; Xiao, J.; Babst, M.; Xu, Z.; Katzmann, D.J. ESCRT-III family members stimulate Vps4ATPase activity directly or via Vta1. Dev. Cell 2008, 14, 50–61.
  73. Tsang, H.T.H.; Connell, J.W.; Brown, S.E.; Thompson, A.; Reid, E.; Sanderson, C.M. A systematic analysis of human CHMP protein interactions: Additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics 2006, 88, 333–346.
  74. Solomons, J.; Sabin, C.; Poudevigne, E.; Usami, Y.; Hulsik, D.L.; Macheboeuf, P.; Hartlieb, B.; Göttlinger, H.; Weissenhorn, W. Structural basis for ESCRT-III CHMP3 recruitment of AMSH. Structure 2011, 19, 1149–1159.
  75. Wollert, T.; Hurley, J.H. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 2010, 464, 864–869.
  76. Kikuchi, K.; Ishii, N.; Asao, H.; Sugamura, K. Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochem. Biophys. Res. Commun. 2003, 306, 637–643.
  77. Davies, C.W.; Paul, L.N.; Kim, M.-I.; Das, C. Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: Nearly identical fold but different stability. J. Mol. Biol. 2011, 413, 416–429.
  78. Ren, G.-M.; Li, J.; Zhang, X.-C.; Wang, Y.; Xiao, Y.; Zhang, X.-Y.; Liu, X.; Zhang, W.; Ma, W.-B.; Zhang, J.; et al. Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases. Sci. Immunol. 2021, 6, eabe2933.
  79. Li, J.; Zhang, Y.; Da Silva Sil Dos Santos, B.; Wang, F.; Ma, Y.; Perez, C.; Yang, Y.; Peng, J.; Cohen, S.M.; Chou, T.-F.; et al. Epidithiodiketopiperazines inhibit protein degradation by targeting proteasome deubiquitinase Rpn11. Cell Chem. Biol. 2018, 25, 1350–1358.e1359.
  80. Song, Y.; Li, S.; Ray, A.; Das, D.S.; Qi, J.; Samur, M.K.; Tai, Y.T.; Munshi, N.; Carrasco, R.D.; Chauhan, D.; et al. Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 2017, 36, 5631–5638.
  81. Li, J.; Yakushi, T.; Parlati, F.; Mackinnon, A.L.; Perez, C.; Ma, Y.; Carter, K.P.; Colayco, S.; Magnuson, G.; Brown, B.; et al. Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nat. Chem. Biol. 2017, 13, 486–493.
  82. Schlierf, A.; Altmann, E.; Quancard, J.; Jefferson, A.B.; Assenberg, R.; Renatus, M.; Jones, M.; Hassiepen, U.; Schaefer, M.; Kiffe, M.; et al. Targeted inhibition of the COP9 signalosome for treatment of cancer. Nat. Commun. 2016, 7, 13166.
  83. Liu, Y.; Liu, X.; Zhang, N.; Yin, M.; Dong, J.; Zeng, Q.; Mao, G.; Song, D.; Liu, L.; Deng, H. Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity inhibiting the deubiquitination activity of CSN5. Acta Pharm. Sin. B 2020, 10, 2299–2312.
  84. Dinarello, C.A. Biologic basis for interleukin-1 in disease. Blood 1996, 87, 2095–2147.
  85. Khare, S.; Dorfleutner, A.; Bryan, N.B.; Yun, C.; Radian, A.D.; de Almeida, L.; Rojanasakul, Y.; Stehlik, C. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 2012, 36, 464–476.
  86. Mikhael, J.R.; Dingli, D.; Roy, V.; Reeder, C.B.; Buadi, F.K.; Hayman, S.R.; Dispenzieri, A.; Fonseca, R.; Sher, T.; Kyle, R.A.; et al. Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin. Proc. 2013, 88, 360–376.
  87. Hadjiaggelidou, C.; Katodritou, E. Regulatory T-cells and multiple myeloma: Implications in tumor immune biology and treatment. J. Clin. Med. 2021, 10, 4588.
  88. Van der Linden, W.A.; Willems, L.I.; Shabaneh, T.B.; Li, N.; Ruben, M.; Florea, B.I.; van der Marel, G.A.; Kaiser, M.; Kisselev, A.F.; Overkleeft, H.S. Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones. Org. Biomol. Chem. 2012, 10, 181–194.
  89. Desvergne, A.; Genin, E.; Maréchal, X.; Gallastegui, N.; Dufau, L.; Richy, N.; Groll, M.; Vidal, J.; Reboud-Ravaux, M. Dimerized linear mimics of a natural cyclopeptide (TMC-95A) are potent noncovalent inhibitors of the eukaryotic 20S proteasome. J. Med. Chem. 2013, 56, 3367–3378.
  90. Kawamura, S.; Unno, Y.; List, A.; Mizuno, A.; Tanaka, M.; Sasaki, T.; Arisawa, M.; Asai, A.; Groll, M.; Shuto, S. Potent proteasome inhibitors derived from the unnatural cis-cyclopropane isomer of Belactosin A: Synthesis, biological activity, and mode of action. J. Med. Chem. 2013, 56, 3689–3700.
  91. Ozcan, S.; Kazi, A.; Marsilio, F.; Fang, B.; Guida, W.C.; Koomen, J.; Lawrence, H.R.; Sebti, S.M. Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors. J. Med. Chem. 2013, 56, 3783–3805.
  92. Dimopoulos, M.A.; Richardson, P.G.; Moreau, P.; Anderson, K.C. Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat. Rev. Clin. Oncol. 2015, 12, 42–54.
  93. Perez, C.; Li, J.; Parlati, F.; Rouffet, M.; Ma, Y.; Mackinnon, A.L.; Chou, T.-F.; Deshaies, R.J.; Cohen, S.M. Discovery of an inhibitor of the proteasome subunit Rpn11. J. Med. Chem. 2017, 60, 1343–1361.
  94. Lauinger, L.; Li, J.; Shostak, A.; Cemel, I.A.; Ha, N.; Zhang, Y.; Merkl, P.E.; Obermeyer, S.; Stankovic-Valentin, N.; Schafmeier, T.; et al. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases. Nat. Chem. Biol. 2017, 13, 709–714.
  95. Li, B.; Wever, W.J.; Walsh, C.T.; Bowers, A.A. Dithiolopyrrolones: Biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics. Nat. Prod. Rep. 2014, 31, 905–923.
  96. Lee, M.-H.; Zhao, R.; Phan, L.; Yeung, S.-C.J. Roles of COP9 signalosome in cancer. Cell Cycle 2011, 10, 3057–3066.
  97. Lee, Y.H.; Judge, A.D.; Seo, D.; Kitade, M.; Gómez-Quiroz, L.E.; Ishikawa, T.; Andersen, J.B.; Kim, B.K.; Marquardt, J.U.; Raggi, C.; et al. Molecular targeting of CSN5 in human hepatocellular carcinoma: A mechanism of therapeutic response. Oncogene 2011, 30, 4175–4184.
  98. Altmann, E.; Erbel, P.; Renatus, M.; Schaefer, M.; Schlierf, A.; Druet, A.; Kieffer, L.; Sorge, M.; Pfister, K.; Hassiepen, U.; et al. Azaindoles as zinc-binding small-molecule inhibitors of the JAMM protease CSN5. Angew. Chem. 2017, 56, 1294–1297.
  99. Ni, W.-J.; Ding, H.-H.; Tang, L.-Q. Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechanisms. Eur. J. Pharmacol. 2015, 760, 103–112.
  100. Liu, B.; Wang, G.; Yang, J.; Pan, X.; Yang, Z.; Zang, L. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes. PLoS ONE 2011, 6, e21416.
  101. Chidambara Murthy, K.N.; Jayaprakasha, G.K.; Patil, B.S. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur. J. Pharmacol. 2012, 688, 14–21.
More